Cabergoline is a generic name of 1-((6-allylergolin-8β-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. The compound and the process for its preparation were disclosed in the U.S. Pat. No. 4,526,892, which is herein incorporated by reference. Another process for manufacture of cabergoline was described in Czech Pat. 287 176. Cabergoline is a selective and long lasting dopamine D2 agonist and it is used for treatment of hyperprolactinemia, parkinsonism, and other related diseases.
Cabergoline was described in several crystalline forms. The first crystalline form of cabergoline was described in II Farmaco, 50, 175-178 (1995), which was latter designated as cabergoline Form I. This form was prepared by crystallisation from diethylether. A new process for preparing the crystalline Form I of cabergoline was described recently in two patent applications WO 01/70740 and WO 03/078392. According to the first one the Form I can be prepared via a new toluene solvate denominated as Form V. The toluene solvate Form V affords the Form I by drying at the temperature from 40 to 65° C., using high vacuum. According to WO 03/078392 the Form I can be prepared via a new toluene hemi-solvate Form X. The solvate X is described in WO 03/078392 as a true solvate having a fixed composition of about 0.5 toluene moles per mole of cabergoline. Form X is unstable and it can be very easily transferred to the Form I even when dried in vacuum at ambient temperature.
Two new anhydrous and unsolvated forms of cabergoline were described recently. Form II, obtained by crystallisation from diethylether and other solvents with similar polarity was described in WO 01/72747. Form VII was obtained by solvent (diethylether, hexane, heptane) mediated phase transition of the Form I at relatively high temperature (from 30 to 80° C.) as described in WO 01/72746. The physical properties of both new forms are very similar to that of the Form I and therefore it does not seem that the new forms can bring any advantage to the use of cabergoline in formulation of drugs.
Crystallisation of cabergoline is difficult, e.g., the crystallisation of the Form II was accomplished by several days cooling and mixing of the solution of purified cabergoline in diethylether. Also the Form I can be obtained by crystallisation from diethylether but its polymorph purity is poor due to the presence of the Form II. Also the yields of the crystalline products obtained by the crystallisation from diethylether are not satisfactory. Therefore, a process producing reproducibly the Form I or any other form and affording high yield of the product is still advisable.
The various crystalline forms have different properties as the result of different arrangement of molecules in the crystal structure, different density of packing, and/or different hydrogen-bond network. Accordingly, individual crystalline forms may be thought of as distinct solids having distinct advantageous and/or disadvantageous physical properties compared to other forms.
All the above mentioned forms are characterised by their IR, DSC, solid state NMR and distinct X-ray powder diffraction patterns defined as a list of 2θ values obtained with certain source of X-ray radiation, which can be easily calculated for any other source of radiation by the Bragge equation. The complete crystal structure determined by X-ray structural analysis was described only for the Form I (Il Farmaco, 50, 175-178 (1995)).